Open AccessCHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity
Author(s) -
Han Seok Ko,
Rachel M. Bailey,
Wanli W. Smith,
Zhaohui Liu,
JooHo Shin,
Yun Il Lee,
Yong Jie Zhang,
Haibing Jiang,
Christopher A. Ross,
Darren J. Moore,
Cam Patterson,
Leonard Petrucelli,
Ted M. Dawson,
Valina L. Dawson
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0810123106
Subject(s) - lrrk2 , ubiquitin ligase , hsp90 , kinase , gene knockdown , mutant , protein kinase domain , hek 293 cells , leucine rich repeat , ubiquitin , proteasome , cytotoxicity , microbiology and biotechnology , hsp70 , chemistry , protein degradation , hsp90 inhibitor , biology , mutation , biochemistry , heat shock protein , apoptosis , gene , in vitro
Mutation inleucine-rich repeat kinase-2 (LRRK2 ) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused byLRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.